ES2617604T3 - Antibodies capable of specifically binding to beta amyloid oligomers, and their use - Google Patents

Antibodies capable of specifically binding to beta amyloid oligomers, and their use Download PDF

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ES2617604T3
ES2617604T3 ES09707511.3T ES09707511T ES2617604T3 ES 2617604 T3 ES2617604 T3 ES 2617604T3 ES 09707511 T ES09707511 T ES 09707511T ES 2617604 T3 ES2617604 T3 ES 2617604T3
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amino acid
antibodies
antibody
acid sequence
seq
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Etsuro Matsubara
Masao Shibata
Tatsuki Yokoseki
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National Center for Geriatrics and Gerontology
Immunas Pharma Inc
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Immunas Pharma Inc
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • G—PHYSICS
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    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
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    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4709—Amyloid plaque core protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
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    • G01N2800/00—Detection or diagnosis of diseases
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Abstract

Un anticuerpo que se une a un oligómero de Aß pero no a un monómero de Aß, en el que el anticuerpo es un anticuerpo monoclonal y se selecciona del grupo que consiste en: (1) un anticuerpo que comprende una cadena H que tiene la secuencia de aminoácidos de la SEQ ID NO: 89 como CDR1, la secuencia de aminoácidos de la SEQ ID NO: 91 como CDR2, y la secuencia de aminoácidos de la SEQ ID NO: 93 como CDR3 y una cadena L que tiene la secuencia de aminoácidos de la SEQ ID NO: 95 como CDR1, la secuencia de aminoácidos de la SEQ ID NO: 97 como CDR2, y la secuencia de aminoácidos de la SEQ ID NO: 99 como CDR3; (2) un anticuerpo que comprende una cadena H que tiene la secuencia de aminoácidos de la SEQ ID NO: 85 como VH y una cadena L que tiene la secuencia de aminoácidos de la SEQ ID NO: 87 como VL; y (3) un anticuerpo que comprende una cadena H que tiene la secuencia de aminoácidos de la SEQ ID NO: 81 y una cadena L que tiene la secuencia de aminoácidos de la SEQ ID NO: 83.An antibody that binds to an Aβ oligomer but not an Aß monomer, in which the antibody is a monoclonal antibody and is selected from the group consisting of: (1) an antibody comprising an H chain having the sequence amino acid of SEQ ID NO: 89 as CDR1, the amino acid sequence of SEQ ID NO: 91 as CDR2, and the amino acid sequence of SEQ ID NO: 93 as CDR3 and an L chain having the amino acid sequence of SEQ ID NO: 95 as CDR1, the amino acid sequence of SEQ ID NO: 97 as CDR2, and the amino acid sequence of SEQ ID NO: 99 as CDR3; (2) an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 85 as VH and an L chain having the amino acid sequence of SEQ ID NO: 87 as VL; and (3) an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 81 and an L chain having the amino acid sequence of SEQ ID NO: 83.

Description

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y Fritz HJ (1987) Methods Enzymol., 154, 350-367, Kunkel, TA (1985) Proc. Natl. Acad. Sci. EE.UU. 82, 488-492, Kunkel (1988) Methods Enzymol., 85, 2763-2766 ) y otros. Las mutaciones de aminoácidos también pueden ocurrir de forma natural. Los anticuerpos de la presente invención también incluyen un anticuerpo que comprende una secuencia de aminoácidos con una o más mutaciones de aminoácidos en la secuencia de aminoácidos de un anticuerpo de la presente invención y que tiene una actividad equivalente a la del anticuerpo de la presente invención. El número de aminoácidos mutados en tales mutantes puede ser generalmente de 50 aminoácidos o menos, preferiblemente 30 aminoácidos o menos, y más preferiblemente diez aminoácidos o menos (por ejemplo, cinco aminoácidos o menos). and Fritz HJ (1987) Methods Enzymol., 154, 350-367, Kunkel, TA (1985) Proc. Natl Acad. Sci. USA 82, 488-492, Kunkel (1988) Methods Enzymol., 85, 2763-2766) and others. Amino acid mutations can also occur naturally. The antibodies of the present invention also include an antibody comprising an amino acid sequence with one or more amino acid mutations in the amino acid sequence of an antibody of the present invention and having an activity equivalent to that of the antibody of the present invention. The number of mutated amino acids in such mutants may generally be 50 amino acids or less, preferably 30 amino acids or less, and more preferably ten amino acids or less (eg, five amino acids or less).

Los residuos de aminoácidos se mutan preferiblemente en otros aminoácidos que conservan las propiedades de las cadenas laterales de aminoácidos. Por ejemplo, los aminoácidos se clasifican como sigue dependiendo de las propiedades de la cadena lateral: aminoácidos hidrófobos (A, I, L, M, F, P, W, Y y V), aminoácidos hidrofílicos (R, D, N, C, E, Q, G, H, K, S y T), aminoácidos con cadenas laterales alifáticas (G, A, V, L, I y P), aminoácidos con cadenas laterales que contienen grupos hidroxilo (S, T y Y), aminoácidos con cadenas laterales que contienen átomos de azufre (C y M), aminoácidos con cadenas laterales que contienen ácido carboxílico y amida (D, N, E y Q), aminoácidos con cadenas laterales básicas (R, K y H), y aminoácidos con cadenas laterales que contienen anillos aromáticos (H, F, Y y W) (los aminoácidos están representados por códigos de una letra entre paréntesis). The amino acid residues are preferably mutated into other amino acids that retain the properties of the amino acid side chains. For example, amino acids are classified as follows depending on the side chain properties: hydrophobic amino acids (A, I, L, M, F, P, W, Y and V), hydrophilic amino acids (R, D, N, C , E, Q, G, H, K, S and T), amino acids with aliphatic side chains (G, A, V, L, I and P), amino acids with side chains containing hydroxyl groups (S, T and Y) , amino acids with side chains containing sulfur atoms (C and M), amino acids with side chains containing carboxylic acid and amide (D, N, E and Q), amino acids with basic side chains (R, K and H), and amino acids with side chains containing aromatic rings (H, F, Y and W) (amino acids are represented by one letter codes in brackets).

Se sabe que un polipéptido que tiene una secuencia de aminoácidos, en la que uno o más residuos de aminoácidos están modificados (suprimidos, añadidos y/o sustituidos con otros aminoácidos) en una cierta secuencia de aminoácidos, conserva su actividad biológica original (función). It is known that a polypeptide having an amino acid sequence, in which one or more amino acid residues are modified (deleted, added and / or substituted with other amino acids) in a certain amino acid sequence, retains its original biological activity (function) .

Además de las modificaciones mencionadas anteriormente, los anticuerpos de la presente invención pueden conjugarse con otras sustancias, siempre que se mantenga la actividad. Ejemplos de las sustancias incluyen péptidos, lípidos, azúcares y cadenas de azúcar, grupos acetilo y polímeros naturales y sintéticos. Estas modificaciones pueden realizarse para conferir funciones adicionales a los anticuerpos, o para estabilizar los anticuerpos. In addition to the modifications mentioned above, the antibodies of the present invention can be conjugated to other substances, provided that the activity is maintained. Examples of the substances include peptides, lipids, sugars and sugar chains, acetyl groups and natural and synthetic polymers. These modifications can be made to confer additional functions to the antibodies, or to stabilize the antibodies.

Los anticuerpos en los que se han añadido varios residuos de aminoácidos a la secuencia de aminoácidos de un anticuerpo de la presente invención incluyen proteínas de fusión que contienen el anticuerpo. En las proteínas de fusión, el anticuerpo se fusiona con otro péptido o proteína. Los métodos para producir una proteína de fusión pueden llevarse a cabo ligando un polinucleótido que codifica un anticuerpo de la presente invención en marco con un polinucleótido que codifica otro péptido o polipéptido e insertándolo en un vector de expresión y expresando el constructo de fusión en un huésped. Para este fin se pueden utilizar técnicas conocidas por los expertos en la técnica. Los péptidos o polipéptidos fusionados con un anticuerpo de la presente invención incluyen, por ejemplo, péptidos conocidos tales como FLAG (Hopp, TP y colaboradores, BioTechnology (1988) 6, 1204-1210), 6x His consistente en seis residuos de histidina (His), 10x His, hemaglutinina de influenza (HA), fragmentos de c-myc humanos, fragmentos de VSV-GP, fragmentos de p18HIV, etiqueta de T7, etiqueta de HSV, etiqueta E, fragmentos de antígeno SV40T, etiqueta lck, fragmentos de α-tubulina, etiqueta B, y fragmentos de Proteína C; glutationa-S transferasa (GST); regiones constantes de inmunoglobulina; β-galactosidasa; y la proteína de unión a la maltosa (MBP), etc. Los polinucleótidos comercialmente disponibles que codifican estos péptidos o polipéptidos pueden fusionarse con polinucleótidos que codifican los anticuerpos de la presente invención y los polipéptidos de fusión pueden producirse expresando los polinucleótidos de fusión así preparados. Antibodies in which several amino acid residues have been added to the amino acid sequence of an antibody of the present invention include fusion proteins containing the antibody. In fusion proteins, the antibody is fused with another peptide or protein. The methods for producing a fusion protein can be carried out by linking a polynucleotide encoding an antibody of the present invention in frame with a polynucleotide encoding another peptide or polypeptide and inserting it into an expression vector and expressing the fusion construct in a host . Techniques known to those skilled in the art can be used for this purpose. Peptides or polypeptides fused with an antibody of the present invention include, for example, known peptides such as FLAG (Hopp, TP et al., BioTechnology (1988) 6, 1204-1210), 6x His consisting of six histidine residues (His ), 10x His, influenza hemagglutinin (HA), human c-myc fragments, VSV-GP fragments, p18HIV fragments, T7 tag, HSV tag, E tag, SV40T antigen fragments, lck tag, fragments of α-tubulin, label B, and Protein C fragments; glutathione-S transferase (GST); constant regions of immunoglobulin; β-galactosidase; and maltose binding protein (MBP), etc. Commercially available polynucleotides encoding these peptides or polypeptides can be fused with polynucleotides encoding the antibodies of the present invention and fusion polypeptides can be produced by expressing the fusion polynucleotides thus prepared.

Los anticuerpos de la presente invención pueden diferir en la secuencia de aminoácidos, peso molecular, presencia The antibodies of the present invention may differ in amino acid sequence, molecular weight, presence

o ausencia de cadenas de azúcar, estructura y similares, dependiendo de la célula o huésped que produce los anticuerpos o del método de purificación. or absence of sugar chains, structure and the like, depending on the cell or host that produces the antibodies or the method of purification.

Los anticuerpos que se unen a un epítopo al que se une un anticuerpo de cualquiera de los (1) a (36) anteriores pueden obtenerse por métodos conocidos por los expertos en la técnica. Por ejemplo, los anticuerpos se pueden obtener (i) determinando el epítopo unido por el anticuerpo de cualquiera de (1) a (36) usando un método convencional, y produciendo los anticuerpos usando un polipéptido que comprende una secuencia de aminoácidos incluida en el epítopo como un inmunógeno; o (ii) determinar los epítopos de anticuerpos producidos por un método convencional, y seleccionar anticuerpos cuyo epítopo es el mismo que el del anticuerpo de uno cualquiera de (1) a (36). Antibodies that bind to an epitope to which an antibody of any of the above (1) to (36) binds can be obtained by methods known to those skilled in the art. For example, antibodies can be obtained (i) by determining the epitope bound by the antibody of any one of (1) to (36) using a conventional method, and producing the antibodies using a polypeptide comprising an amino acid sequence included in the epitope as an immunogen; or (ii) determine the epitopes of antibodies produced by a conventional method, and select antibodies whose epitope is the same as that of the antibody of any one of (1) to (36).

Los anticuerpos mencionados anteriormente de (1) a (38) también incluyen cualquier tipo de anticuerpos tales como los minicuerpos anteriormente descritos, anticuerpos con secuencias de aminoácidos modificadas tales como anticuerpos humanizados y anticuerpos quiméricos, anticuerpos animales no humanos, anticuerpos humanos, anticuerpos modificados conjugados con otras moléculas (por ejemplo, polímeros tales como polietilenglicol) y anticuerpos modificados en la cadena de azúcar. The antibodies mentioned above from (1) to (38) also include any type of antibodies such as the minibodies described above, antibodies with modified amino acid sequences such as humanized antibodies and chimeric antibodies, non-human animal antibodies, human antibodies, conjugated modified antibodies with other molecules (for example, polymers such as polyethylene glycol) and modified antibodies in the sugar chain.

En una realización preferida, los anticuerpos de la presente invención son anticuerpos modificados tales como anticuerpos quiméricos y anticuerpos humanizados. Ejemplos de anticuerpos preferidos incluyen (i) un anticuerpo quimérico cuya región variable se deriva del anticuerpo 6E4 y cuya región constante se deriva de una inmunoglobulina humana; y (ii) un anticuerpo humanizado cuya CDR se deriva del anticuerpo 6E4, y cuyo FR se In a preferred embodiment, the antibodies of the present invention are modified antibodies such as chimeric antibodies and humanized antibodies. Examples of preferred antibodies include (i) a chimeric antibody whose variable region is derived from the 6E4 antibody and whose constant region is derived from a human immunoglobulin; and (ii) a humanized antibody whose CDR is derived from the 6E4 antibody, and whose FR is

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Claims (1)

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ES09707511.3T 2008-02-08 2009-02-06 Antibodies capable of specifically binding to beta amyloid oligomers, and their use Active ES2617604T3 (en)

Applications Claiming Priority (7)

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JP2008028386 2008-02-08
JP2008028386 2008-02-08
US8554508P 2008-08-01 2008-08-01
US85545 2008-08-01
JP2008201058 2008-08-04
JP2008201058 2008-08-04
PCT/JP2009/052039 WO2009099176A1 (en) 2008-02-08 2009-02-06 Antibody capable of binding specifically to aβ-oligomer, and use thereof

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CA (1) CA2714413C (en)
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